The basis of this proposed research arises from the observation of the behavioral central nervous system depressant activity of gamma-hydroxybutyrate (GHB) demonstrated in a number of animal species, including man; the observation of an isozyme of lactic dehydrogenase in mammalian brain involved in the conversion of succinic semialdehyde to GHB; the demonstration of the endogenous occurrence of GHB in rat, guinea pig, cat and bovine brain and the observation that exogenously administered GHB produces a marked and selective increase in striatal dopamine in the rat as a result of its ability to produce a reversible lesion in the nigro-neostriatal pathway. Thus normal mammalian brain contains and is capable of forming an endogenous compound which when administered systemically produces behavioral depression and an interruption of impulse flow in dopaminergic neurons. It is our aim to see if GHB occurs endogenously in human brain; to study the metabolic routes for synthesis and degradation of GHB; to try to determine the functional role this compound plays in the central nervous system by investigating its possible role in normal, abnormal or drug-induced states of "sleep" and hibernation; to investigate the mechanism by which GHB ultimately causes a suppression of impulse flow in the nigro-neostriatal pathway and to see if this action is specific for dopamine-containing neurons as opposed to norepinephrine or serotonin containing neurons; to determine the mechanism responsible for the rapid increase in dopamine synthesis resulting from an abolition of impulse flow in the dopaminergic pathway due to pharmacological treatment with GHB or mechanical interruption of this pathway; to investigate if all dopaminergic neurons respond in a similar fashion to the systemic administration of GHB; and finally to learn more about the biochemical organization and regulatory control of monoaminergic neurons in the central nervous system. BIBLIOGRAPHIC REFERENCES: Roth, R.H. Morgenroth, V.H., III and Murrin, L.C.: Effects of Antipsychotic Drugs and Impulse Flow on the Kinetics of Striatal Tyrosine Hydroxylase. In Antipsychotic Drugs, Pharmacodynamics and Pharmacokinetics. Wenner-Gren Center International Symposium Series, Pergamon Press, Ltd., New York, 1975.